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Too much of a good thing:
Excess exercise can harm mitochondria
Mark W. Pataky1 and K. Sreekumaran Nair1,*
1Division of Endocrinology and Metabolism, Mayo Clinic, Rochester, MN, USA
*Correspondence: nair@mayo.edu
https://doi.org/10.1016/j.cmet.2021.04.008
Health benefits of aerobic exercise are indisputable and are closely related to the maintenance of mitochon-
drial energy homeostasis and insulin sensitivity. Flockhart et al. (2021) demonstrate, however, that a high vol-
ume of high-intensity aerobic exercise adversely affects mitochondrial function and may cause impaired
glucose tolerance.
In the ancient Sanskrit scriptures,
‘‘Amrita’’ is a nectar that bestows immor-
tality but in excess is a poison. Exercise is
a fundamental therapeutic recommenda-
tion to ameliorate many cardio-metabolic
disorders, but like other therapeutic rem-
edies it is harmful in excess. A principal ef-
fect of aerobic exercise is the enhance-
ment of mitochondrial function in
skeletal muscle (Holloszy, 1967), as well
as in other organs, including the brain
(Ruegsegger et al., 2019). Thus, exercise
counteracts a decline of metabolic and
other physiological functions of aging
and insulin-resistant states (Cartee et al.,
2016). In the current issue of Cell Meta-
bolism, Flockhart et al. (2021) show that
as the volume of high-intensity aerobic in-
terval training (HIIT) increases to ‘‘exces-
sive’’ levels, mitochondrial function de-
clines, concurrent with impairment of
glucose tolerance, but upon recovery to
normal exercise levels the mitochondria
also recover normal functional capacity
(Figure 1).
In their study, eleven (six female and
five male) physically active and healthy
participants performed 3 weeks of HIIT
with progressively increasing volume
and frequency, followed by a fourth
week of recovery with reduced training
load. During the third week, when partici-
pants performed particularly frequent and
high volumes of HIIT, improvements in
power output stagnated. Muscle biopsies
obtained 14 h following the exercise ses-
sions showed reduced mitochondrial
respiration using carbohydrate and fat
substrates. The decline in muscle mito-
chondrial respiration was associated
with impairment of glucose tolerance.
However, oral glucose tolerance tests
represent not only muscle glucose up-
take, but also endogenous glucose pro-
duction and insulin secretion. The obser-
vation that muscle hexokinase activity
was elevated, while oxidative metabolism
was reduced at 14 h following excessive
training, may represent activation of
anaerobic glycolysis. However, lactate
levels were not elevated during excessive
training, suggesting activation of the Cori
cycle (Nielsen et al., 2002), which involves
the shunting of lactate to the liver for
gluconeogenesis with glucose released
to the circulation, but this notion has to
be experimentally tested by future
studies. The capacity for greater glucose
transport following excessive training is
indicated by increased content of the
glucose transporter GLUT4. Of course, a
better measure of exercise-mediated
glucose transport capacity is the cell sur-
face level of GLUT4 after exercise. How-
ever, muscle samples were collected
14 h following exercise, long after the ex-
ercise-mediated effect on glucose trans-
port takes place (Wallberg-Henriksson
et al., 1988). Elevation of total GLUT4,
glycogen content, and glycogen synthase
suggests that excessive HIIT did not
adversely affect the muscle’s capacity to
handle glucose. Despite the evidence for
increased glucose storage, transport,
and glycolysis in skeletal muscle, glucose
tolerance was reduced with excessive
training. It will be important to know
whether reduced mitochondrial capacity
for carbohydrate and fat oxidation
causes, or is a result of, impaired glucose
tolerance following excessive HIIT.
Flockhart et al. also assessed whether
oxidative stress occurred, which could
cause insulin resistance and oxidative
Cell Metabolism 33, May 4, 2021 ª 2021 Elsevier Inc. 847
damage to proteins. Interestingly, they
found in their cohort of healthy partici-
pants 14 h following excessive training
that reactive oxygen species (ROS) pro-
duction was paradoxically reduced. This
was interpreted as a ‘‘compensatory par-
tial shutdown of mitochondrial meta-
bolism to reduce overall ROS produc-
tion,’’ implying that in healthy muscle,
the stress imposed during excessive
training caused the mitochondria to
reduce respiration as a protective mecha-
nism to maintain a balanced redox state,
preventing excessive cellular damage.
Consequently, reduced mitochondrial
respiration occurred concurrent to
impaired glucose tolerance, but the rela-
tionship between maximal mitochondrial
respiration and glucose tolerance is com-
plex. ROS can have bidirectional effects
on insulin action, as both an acute reduc-
tion in ROS and chronically elevated ROS
can potentially cause insulin resistance.
Further, insulin-induced ROS in vivo pro-
motes insulin signaling and sensitivity
(Tiganis, 2011).
Of interest, despite the reduced mito-
chondrial oxidative function by excessive
training, the activity of citrate synthase
(CS) was higher, despite no change in
CS protein abundance. Although CS is
often used as a measure of mitochondrial
protein content, this nuclear DNA-en-
coded protein is critical for the TCA cycle,
but not directly involved in the electron
transport chain (ETC) or oxidative phos-
phorylation. The abundance of multiple
proteins directly involved in mitochondrial
oxidative metabolism (i.e., Complexes I,
II, III, and IV) was significantly increased
after excessive training. Furthermore,
mitochondrial fusion markers were
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Figure 1. Impairment of muscle mitochondrial function with excessive high-intensity
aerobic exercise training
Flockhart et al. have shown that upon increasing exercise training from light to moderate volume/intensity,
mitochondria enhance respiratory capacity. However, when exercise training reaches excessive levels the
mitochondrial function declines, with currently unknown intrinsic molecular defects. As exercise training
returns to normal levels in the recovery period after excessive training, mitochondria can quickly regain
normal functional capacity.
elevated during excessive training, with
no change in mitochondrial fission
markers, suggesting that a rapid
increase in exercise volume caused no
disruption in the mitochondrial network.
As a result of these observations, a criti-
cally important question is as follows:
what contributes to the reduced mito-
chondrial function observed 14 h
following high-volume HIIT?
A reduction in both mitochondrial respi-
ration and ROS emission is intriguing, but
the authors also found no change in abun-
dance of SOD2, GPX, CAT, or HO-1-1,
which are enzymes in the mitochondrial
antioxidant defense system. However,
the activities of these enzymes were not
measured. Because H2O2 production
was reduced, it would be logical to
consider whether the activities of these
enzymes were enhanced during exces-
sive training. The authors proposed that
the reduction in mitochondrial respiration
was due to a compensatory mechanism
to spare the cell from excessive oxidative
stress. Nrf2 protein content (critical for
redox homeostasis) is reduced after
excessive training. Therefore, it is possible
that antioxidative enzyme activities were
reduced. What molecular mechanisms
could cause such a disruptive effect to
mitochondrial enzymes after excessive
training? One clue is that mitochondrial
ROS production and respiration following
excessive training are quickly reversible,
848 Cell Metabolism 33, May 4, 2021
as within 1 week of reduced volume HIIT
mitochondrial H2O2 production and respi-
ration began to return to normal levels.
Perhaps the likely cause of reduced mito-
chondrial function following excessive
training is altered proteome homeostasis,
including an accumulation of damaged
proteins due to irreversible modifications,
or a defect in posttranslational modifica-
tions such as phosphorylation, lysine-
acetylation, or lipidation, which activate
mitochondrial proteome function. Then,
upon the recovery period following exces-
sive training, these protein modifications
may reverse. Of course, this hypothesis
will require solid proof based on further
investigations.
It is important to appreciate that the
third week of high-volume exercise was
initiated without allowing the body to
adapt to the moderate exercise. Meta-
bolic adaptation to HIIT involves
enhanced mitochondrial biogenesis at
transcriptional and translational levels
(Robinson et al., 2017), with hormonal (in-
sulin) and nutritional factors (amino acids)
also playing critical roles in mitochondrial
biogenesis (Ruegsegger et al., 2018).
Mitochondrial quality is determined by
the ability to remove damaged proteins
efficiently and replace them with newly
synthesized proteins. An optimum recov-
ery period is needed to achieve accretion
of sufficient and highly functional mito-
chondrial proteins. The optimum intensity
Previews
of HIIT and length of recovery period that
are needed to achieve this remain to be
fully understood, especially since this
may vary widely among individuals of
different ages, sexes, and clinical condi-
tions (such as type 2 diabetes, heart
failure, etc.). The current studies have suf-
ficiently stimulated a need to address
important questions on the optimum vol-
ume and adaptation period to HIIT not
only in healthy but also in various age
groups and health status. Too much and
too rapid of an increase in intensity of ex-
ercise are stressful and harmful to health,
but too little physical activity is also not
healthy.
DECLARATION OF INTERESTS
The authors declare no competing interests.
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